DNA repair, Cell cycle Checkpoints and Apoptosis and Bladder Cancer Risk

描述（申请人提供）：我的长期目标是成为一名独立的分子流行病学家，在遗传学和先进的统计方法方面受过深入的训练，能够分析高通量的基因变异数据，探索基因-基因和基因-环境在癌症易感性中的相互作用。我的职业发展计划包括教学课程/研讨会，与人类遗传学、癌症生物学和高级统计方法领域的导师会面。我的研究方向是膀胱癌（BC）的遗传易感性。我建议利用一项正在进行的病例对照研究的流行病学和遗传标记数据，“膀胱癌遗传易感性标记”（R01 CA74880,PI:Xifeng）。吴)。父母研究目前包括2500多名，主要是高加索人，BC病例和对照，性别，年龄和种族相匹配。我的目标是利用最先进的基因分型技术和新的统计和生物信息学工具，确定新的基因座赋予膀胱癌易感性。具体目标是：1)通过使用Illumina Golden Gate Assay将800例白种人病例和800例白种人对照中的DNA修复、细胞周期控制和凋亡途径基因中的2112个标记snp扩展到原来的45个潜在功能snp，以提高我在遗传学和统计学方面的知识和技能，以识别新的遗传位点作为BC的易感性标记；2)评估作为易感性标记的单倍型和双倍型；3)利用生物信息学工具评估snp在DNA修复、细胞周期控制和凋亡通路中的功能意义，并将DNA修复和细胞周期控制的基因型数据与表型分析得出的功能数据相关联。第二个目标是应用分层模型来完善风险评估，并应用新的机器学习工具来探索影响BC风险的任何基因-环境和基因-基因相互作用。我的项目补充了父母的资助，因为它：1)在父母的资助中增加了对潜在功能snp的标记；2)增加单倍型分析；3)提出新的统计和生物信息学方法。相关性：膀胱癌是一种与烟草有关的癌症，是美国男性第四大常见癌症。事实上，只有一小部分吸烟者患膀胱癌，这表明遗传易感性的疾病。这项研究将确定新的遗传标记可能作为生物标记物用于识别高风险人群，然后可以针对干预计划。

DESCRIPTION (provided by applicant): My long-term goal is to become an independent molecular epidemiologist with in-depth training in genetics and advanced statistical methods in order to be able to analyze high throughput gene variant data to explore gene-gene and gene-environment interactions in cancer susceptibility. My career development plan include didatic courses/seminars, meetings with mentors in the areas of human genetics, cancer biology and advanced statistical methods. My research proposal will focus on genetic susceptibility of bladder cancer (BC). I propose to capitalize on availability of epidemiologic and genetic marker data from an on-going case-control study, "Markers of Genetic Susceptibility to Bladder Cancer"(R01 CA74880,PI:Xifeng. Wu). The parent study currently include over 2,500,mostly Caucasian, BC cases and controls, matched on sex, age and ethnicity. My goal is to identify novel loci that confer bladder cancer susceptibility using state-of-the-art genotyping technology and novel statistical and bioinformatics tools. The Specific Aims are: 1) To enhance my knowledge and skills in genetics and statistics to identify novel genetic loci as susceptibility markers of BC by extending the original45 potential functional SNPs to include additional 2112 tagging SNPs in genes in the DNA repair, cell cycle control and apoptotic pathways in 800 Caucasian cases and 800 Caucasian controls using the Illumina Golden Gate Assay; 2) To assess haplotypes and diplotypes as markers of susceptibility; 3) To use bioinformatics tools to assess functional significance of SNPs in the DNA repair, cell cycle control and apoptotic pathways and to correlate genotype data of DNA repair and cell cycle control with functional data derived from phenotypic assays. The secondary aim is to apply hierarchical models to refine risk assessment and to apply novel machine-learning tools to explore any gene-environment and gene-gene interactions influencing BC risk. My project complements the parent grant in that it: 1) adds tagging SNPs to potential functional SNPs addressed in the parent grant; 2) adds haplotype analyses; 3) proposes novel statistical and bioinformatics approaches. RELEVANCE: Bladder cancer is a tobacco-related cancer which is the fourth most common cancer in men in U.S. The fact that only a fraction of smokers develop bladder cancer indicating genetic susceptibility to the disease. This study will identify novel genetic markers may be useful as biomarkers to identify high-risk populations that could then be targeted for intervention programs.